Cost-effectiveness of antenatal corticosteroids and tocolytic agents in the management of preterm birth: A systematic review

Summary Background Preterm birth is a leading cause of neonatal mortality and morbidity, and imposes high health and societal costs. Antenatal corticosteroids (ACS) to accelerate fetal lung maturation are commonly used in conjunction with tocolytics for arresting preterm labour in women at risk of imminent preterm birth. Methods We conducted a systematic review on the cost-effectiveness of ACS and/or tocolytics as part of preterm birth management. We systematically searched MEDLINE and Embase (December 2021), as well as a maternal health economic evidence repository collated from NHS Economic Evaluation Database, EconLit, PubMed, Embase, CINAHL and PsycInfo, with no date cutoff. Eligible studies were economic evaluations of ACS and/or tocolytics for preterm birth. Two reviewers independently screened citations, extracted data on cost-effectiveness and assessed study quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Findings 35 studies were included: 11 studies on ACS, eight on tocolytics to facilitate ACS administration, 12 on acute and maintenance tocolysis, and four studies on a combination of ACS and tocolytics. ACS was cost-effective prior to 34 weeks’ gestation, but economic evidence on ACS use at 34-<37 weeks was conflicting. No single tocolytic was identified as the most cost-effective. Studies disagreed on whether ACS and tocolytic in combination were cost-saving when compared to no intervention. Interpretation ACS use prior to 34 weeks’ gestation appears cost-effective. Further studies are required to identify what (if any) tocolytic option is most cost-effective for facilitating ACS administration, and the economic consequences of ACS use in the late preterm period. Funding UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by WHO.


Introduction
An estimated 14.84 million infants are born preterm worldwide every year. 1 Complications relating to preterm birth are the leading cause of mortality in children under 5 worldwide. 2 Neonatal complications of preterm birth can include respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH), and several other serious morbidities. 3 Over the longer term, babies born preterm have higher rates of neurodevelopmental disabilities, as well as more frequent hospitalisations, incurring large societal costs. 3 In Australia, an estimated A$1.4 billion is spent annually on healthcare and educational costs associated with preterm children until 18 years of age. 4 In 2015 WHO released evidence-based guidelines on the use of interventions to improve preterm birth outcomes. 5 These interventions include the use of antenatal corticosteroids (ACS) and tocolytics, as well as several interventions used in the care of preterm infants. ACS (typically intramuscular dexamethasone or betamethasone) can cross the placenta and accelerate fetal lung maturation. 6 When administered to women at risk of imminent preterm birth prior to 34 weeks' gestation, ACS can prevent perinatal and neonatal death, RDS and IVH, without causing maternal or newborn harms. 7 WHO thus recommended that ACS can be used for this indication, provided that a minimum standard of maternal and preterm newborn care is available. 5 While WHO does not recommend the routine use of tocolytics for women in preterm labour (in light of the lack of substantive effects on perinatal health outcomes), the guideline panel acknowledged that some tocolytic options prolong pregnancy by 2-7 days, providing a window for ACS administration or in-utero transfer to a higher-level care facility. 8 In such instances, nifedipine is the preferred tocolytic drug. 5 Acute tocolysis is recommended in several high-income countries, 9 and observational evidence indicates that some tocolytics (such as betamimetics and calcium channel blockers) are used for preterm labour management in lowand middle-income countries (LMICs). 10 Evaluating healthcare interventions from both health and economic perspectives allows policymakers, clinicians and other stakeholders to identify the most efficient (or cost-effective) healthcare strategies to maximise health benefits at a population level. 11 In resource-limited settings, cost is often a key consideration in the decision to implement interventions at scale. While several economic evaluations have been conducted on ACS and tocolytics in preterm birth, to date no review has synthesized all available economic evidence. Cochrane systematic reviews on the effectiveness of ACS and different tocolytic options for preterm birth did not pre-specify outcomes related to cost or cost-effectiveness. 7,[12][13][14][15][16][17][18][19] In this study, we aimed to synthesize all available evidence on the cost-effectiveness of ACS and tocolytics as individual or co-interventions for improving preterm birth outcomes.

Methods
This review is reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 checklist. 20 As a systematic review of published studies, ethical approval was not required nor sought. The scoping review protocol is registered at DOI: 10.17605/OSF.IO/JWTGE.

Eligibility criteria
Eligible studies were those that assessed the cost-effectiveness of ACS and/or tocolytic therapy for preterm

Research in context
Evidence before this study Efficacy evidence indicates that antenatal corticosteroids (ACS) prior to 34 weeks' gestation for women at risk of imminent preterm birth significantly reduces neonatal morbidity and mortality. Though there is relatively less evidence on effects of ACS in the late preterm period (34 to <37 weeks' gestation), they might reduce neonatal respiratory morbidity but could also increase neonatal hypoglycaemia. Multiple drug classes have been evaluated for tocolysis in women with spontaneous preterm labour. Some tocolytic drugs can effectively prolong pregnancy − providing time for ACS administration and/or transfer to higher level care − but tocolytic drugs have not yet been shown to independently improve substantive perinatal health outcomes. We identified a 2009 health technology assessment that broadly evaluated the economic effects of test-treatment interventions in preterm labour, however the cost-effectiveness of ACS and/or tocolytics only were not specifically reported.

Added value of this study
We searched MEDLINE, Embase and a repository of maternal health economic evaluations derived from six economic and health databases. Available economic studies of ACS and/or tocolytics were largely conducted in high-income countries. ACS prior to 34 weeks' gestation appears cost-effective, though economic evidence from the USA on ACS use in late preterm birth indicates that its cost-effectiveness varies depending on which health outcomes are considered. Some studies suggest that tocolysis to facilitate ACS administration was not cost-saving, but may be cost-effective. No single tocolytic option was identified as dominant in the management of spontaneous preterm labour.
Implications of all the available evidence ACS prior to 34 weeks' gestation is cost-effective in high-income countries. There is limited economic evidence from low-to-middle-income countries, though modelling suggests ACS implementation and scale up would likely be cost-effective in these contexts. In light of the limited and conflicting evidence on tocolytics for spontaneous preterm labour, it is not possible to conclude what (if any) tocolytic option is the most costeffective. Further, robust economic evaluations on ACS at 34-<37 weeks' gestation, tocolytics alone, and ACS and tocolytics in combination are required, particularly those that explore cost-effectiveness in resource-limited settings.
birth. The primary outcome of interest was the incremental cost effectiveness ratio (ICER) (i.e., the change in cost and effectiveness when an intervention is compared to alternative intervention) of these two interventions, whether compared to no treatment or alternative treatment. We also extracted any available data on other relevant health economic measures, such as estimates of quality-adjusted life-years (QALYs) (years of life lived with perfect health), cost, cost savings, or cost benefit.

Information sources, search strategy and selection process
Our research team has previously conducted a broad scoping review to identify economic evaluations of any maternal health intervention. 21 In brief, eligible studies were sought from specialist health economic databases (NHS Economic Evaluation Database and EconLit) and medical databases (PubMed, Embase, CINAHL, and PsycInfo) using a structured search conducted on 20 November 2020. Eligible studies for that scoping review were full economic evaluations that assessed cost-benefit, cost-effectiveness, and/or cost-utility for women at any stage of pregnancy, childbirth, and up to six weeks postpartum. Studies of any intervention directed primarily towards improving maternal health outcomes were eligible, though interventions related to pre-conception care, ectopic pregnancy, early pregnancy loss, or management of abortion were not included. The scoping review had no restrictions in terms of comparator, publication date, country, or language. For the current review of cost-effectiveness studies of ACS or tocolytic therapy, we searched all 923 studies included in the scoping review database using synonyms of 'antenatal corticosteroid' and 'tocolytic', as well as reviewing any study conducted in women experiencing preterm birth (Appendix S1).
In order to update the search with more recent studies and capture studies not indexed by NHS EED, we searched MEDLINE and Embase for relevant studies with no setting or language restrictions on 14 December 2021. The search strategy was designed with assistance from an information specialist, using search terms related to 'antenatal corticosteroid', 'tocolytic', 'preterm birth' and 'economic evaluation' (Appendix S1).
For both searches at least two review authors independently screened all titles and abstracts, assessed full texts of potentially eligible studies, and extracted data (disagreements were resolved by discussion). Covidence software was used for title and abstract and full text screening. Studies were included if the intervention was directly related to use of an ACS and/or tocolytic, regardless of drug type. Studies related to progestational agents were not included as they pertained to prevention -rather than management -of preterm labour. In addition, reference lists of each of the included studies were reviewed to identify any additional eligible studies.
Data extraction, synthesis, and quality assessment Data were extracted by two authors independently using a pre-designed Excel spreadsheet adapted from a 2021 systematic review of cost-effectiveness studies by Aziz et al. 22 Extracted data were primarily descriptive, including: country, setting, funding, study design, economic evaluation type, analytic perspective, currency, year of costs, time horizon, and data sources used. Available cost data and incremental cost-effectiveness ratios (ICER) were extracted for each study. Any disagreements on data extraction were resolved through discussion or consultation with a third author. Costs were reported as described in an included study and were not converted to a single currency or year of costs. Results were summarised in tables and reported narratively. Methodological quality of included studies was assessed using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Taskforce Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, 23 as recommended by Wijnen et al. 24 Three quality categories were adopted for the CHEERS score (a maximum score of 24) − high (>75%), moderate (50-74%), and low (<50%) as used by Zakiyah et al. 25 Two authors independently assessed the quality of each study using this framework, with disagreements resolved through discussion or consulting a third author.
This work was financially supported by UNDP/ UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme of the World Health Organization.

Role of funding
The funder organization had no direct role in the study design, data collection, analysis, or interpretation. Two staff members of HRP/WHO were co-authors, and provided input to the study design, analysis and findings.

Characteristics of included studies
The combined searches identified 1083 citations, of which 34 were eligible ( Figure 1). Two further studies were identified from reference list review of the included studies. A total of 35 studies from 36 citations were included in this review. One study was an abstract only and the full text could not be recovered. Among included studies, 11 pertained only to use of ACS (Table 1), 20 to use of tocolytics (Table 2), and four involved a combination of ACS and tocolytics (Table 3).

Antenatal corticosteroids
Preterm birth prior to 34 weeks' gestation. Five studies examined cost-effectiveness of ACS prior to 34 weeks' gestation, and were conducted in the United States of America (USA) (two studies), the United Kingdom (UK), the Netherlands and Brazil (Table 1). 26,[28][29][30][31] Morales et al (1986) considered dexamethasone only, 30 Ogata et al (2016) considered either betamethasone or dexamethasone, 26 and three studies did not specify. 28,29,31 Three studies used decision modelling techniques 26,28,31 while two studies considered costs alongside a retrospective cohort study 29 and a randomised controlled trial 30 respectively. Ogata et al (2016) specified a provider perspective 26 while the other four studies did not specify a perspective. [28][29][30][31] All five studies used a short-term time horizon for costs and outcomes (until neonatal discharge from hospital). Methodological quality was high for one study, 26 moderate for three studies, 28,29,31 and low for one study. 30 The Ogata et al study in Brazil (2016) found that ACS significantly reduced most neonatal morbidity outcomes and hospitalisation costs in infants who survived hospitalisation, except for late-onset sepsis where the probability increased by 2¢5% (Table 4). 26 Simpson et al (1995) found that in USA hospital settings ACS reduced hospital costs, deaths, and specific neonatal morbidities (index cases) in all infants born <2kg, as well as in premature infants at 28 to 31 weeks. In premature infants <28 weeks, the ACS treatment group had fewer deaths but a greater number of index cases; however, ACS was still cost-saving in terms of hospital costs. 28 In the Netherlands, Egberts et al (1992) found that ACS reduced deaths, cases of RDS, and costs per survivor, but more survivors meant total costs increased compared to no           treatment (24300 DFL per extra survivor). 29 In the USA in 1986, Morales et al reported ACS reduced costs, hospitalisation time, RDS cases, and IVH cases compared to no treatment. 30 Mugford et al (1991) found that in the UK ACS reduced deaths, RDS cases, and costs compared to no treatment. 31 Preterm birth at 34 to <37 weeks' gestation. All three studies on ACS cost-effectiveness at 34 to <37 weeks' gestation were undertaken in the USA (Table 1). [32][33][34] Bastek et al (2012) used a literature review to construct a decision model considering ACS use from a single payer perspective. 33 The other two studies used outcomes related to betamethasone use from the Antenatal Late Preterm Steroids (ALPS) trial: 62 Gyamfi-Bannerman et al (2019) used a third-party funder perspective, 34 while Rosenbloom et al (2020) used a health sector perspective. 32 Bastek et al examined a lifetime horizon for costs and effects, 33 while the other two studies used short time horizons − the first 72 hours 34 or first 7¢5 days of the neonatal period, 32 respectively. All three studies were assessed as high methodological quality.
Bastek et al reported that the ICER for a full course of ACS (compared to no ACS) favoured the full course of ACS at 34, 35, and 36 weeks using a threshold of $100,000/QALY; a partial course of ACS was not costeffective (Table 4). 33 When comparing ACS to no ACS at 34 weeks alone, the ICER was $62,888Á25/QALY, compared to $64,425Á67/QALY at 35 weeks, and $64,793Á71/QALY at 36 weeks in the base case − however, these were not robust across all variations of acute and chronic disease distribution. Sensitivity analyses restricted to distributions associated with acute respiratory disease demonstrated 95% confidence in ACS willingness-to-pay thresholds of >$64,677 at 34 weeks, > $65,700 at 35 weeks, and >$65,819 at 36 weeks. Gyamfi-Bannerman et al concluded that compared to placebo, betamethasone was more effective and decreased total mean costs for each woman-infant pair. 34 Rosenbloom et al used the same trial data as Gyamfi-Bannerman et al and reported that betamethasone was dominated by no ACS. 32 This can be attributed to Gyamfi-Bannerman et al costing the primary trial outcome only (a composite of neonatal respiratory treatment or stillbirth or neonatal death in the first 72 hours after birth), while Rosenbloom et al considered costs of additional outcomes (neonatal hypoglycaemia, which increased with betamethasone) alongside RDS and transient tachypnoea of the newborn (TTN), and derived utilities for each outcome from the literature to calculate QALYs. They reported ACS as being slightly more expensive and generating less QALYs than placebo.
Preterm birth (broad or unspecified gestation). One study from the USA by Johnson et al (1981) examined ACS use (betamethasone) from 26 to 35 weeks' gestation considering costs alongside a retrospective cohort study. 35 Newborn effects until discharge from hospital were considered, though the perspective was not specified. Methodological quality was assessed as moderate. The authors reported a significantly lower mortality in the two smallest birthweight categories (750-999g, 1000-1249g) without statistically significant difference in hospital charges. Conversely, infants with birth weights between 1250 and 1749g (30-32 weeks' gestation) incurred significantly lower hospital charges despite no difference in mortality, suggesting ACS is dominant when birth-weight categories are combined.
Two other studies conducted in Ethiopia and South Africa examined ACS use in preterm birth without specifying the gestational age range, using the Lives Saved tool (LiST) for cost-effectiveness analysis. 36,37 The study in Ethiopia (high methodological quality) considered betamethasone and used a provider perspective, while the South Africa study (moderate methodological quality) did not specify either of these. Neither study reported the time horizon. Memirie et al (2019) found that increasing coverage of ACS in preterm labour by 20% in Ethiopia was highly cost-effective at $98 per DALY averted. 36 Michalow et al (2015) found that increasing coverage of ACS from 20% to 100% in South Africa was highly cost-effective at $37 per life-year saved. 37 Tocolytics Tocolytics to facilitate ACS administration. Eight studies assessed cost-effectiveness for tocolytics when used to prolong pregnancy for at least 48 hours, of which seven explicitly stated this was to facilitate ACS administration 38,39,[41][42][43][44][45] − the remaining study (abstract only) did not specify the reason (Table 2). 40 All were conducted in high-income countries (Belgium, Canada, Czech Republic, Germany, Italy, Netherlands, Spain, and USA). Three studies conducted a cost-effectiveness analysis alongside a randomised trial, 40,42,43 three studies constructed decision tree models using cost and outcome estimates from the literature, 38,39,41 and two studies by the same group conducted cost-minimisation analyses alongside a systematic review. 44,45 Analytical perspective varied between studies, including societal, 42 hospital, 38,43 health system, 41 health insurance company, 39,40 and multiple perspectives (hospital, payer and combined hospital and payer). 44,45 Time horizons were generally short-term for both costs and outcomes − most studies focused on the 48 hours from time of hospitalisation or commencement of tocolysis. [38][39][40][41][42][43][44][45] One study examined outcomes until neonatal discharge from neonatal intensive care unit (NICU), 43 one study was until six weeks postpartum, 42 and one study considered hearing loss up to five years of age. 39 Methodological quality was generally high (six studies) with one study of moderate quality; one study could not be fully assessed (abstract only). 40 Most studies compared types of tocolytic agents and administration methods; only one study compared tocolysis with placebo, suggesting that transdermal GTN patches may be dominant with lower NICU admissions and associated costs ( Table 5). 43 Of the five studies comparing atosiban to different betamimetics (ritodrine, fenoterol, fenoterol with magnesium sulphate, hexoprenaline, isoxuprine), findings were mixed − two studies found atosiban to be equivalent to the comparator, 39,40 two studies by the same lead author in different country settings (Italy and Germany) found that atosiban achieved equal effectiveness but at less cost than a betamimetic due to its superior safety profile, 44,45 and one study concluded that ritodrine was more cost-effective as a first-line tocolytic than atosiban. 41 One study comparing nifedipine and atosiban concluded that, in singleton pregnancies, nifedipine generated lower costs due to fewer NICU admissions; in multiple pregnancies, nifedipine was more effective and less costly. 42 One study compared four agents (indomethacin, nifedipine, subcutaneous terbutaline, magnesium sulphate) and found indomethacin to be dominant in the base case, with nifedipine dominant in sensitivity analyses. 38 Acute and maintenance tocolysis. Twelve studies examined tocolytic use for acute and maintenance tocolysis (Table 2). Most studies compared types of tocolytic agents and administration methods, though two studies from the USA in the 1980's compared tocolysis with no tocolysis. 56,57 Five studies − all conducted in the USA between 2001 and 2009 − considered acute and maintenance tocolysis in women with recurrent preterm labour, [46][47][48][49][50] three studies from the USA, and Serbia and Montenegro, considered acute and maintenance tocolysis in preterm labour, 52,56,57 two studies from Chile and the USA examined acute tocolysis with subsequent surveillance, 53,55 one study compared intravenous followed by continuous oral fenoterol with intravenous fenoterol for 48-72 hours only, 54 and one study examined maintenance with subcutaneous terbutaline in an inpatient versus outpatient setting. 51 Five studies used patient data from the same Matria Healthcare database 46,47,[49][50][51] and seven studies conducted costeffectiveness analyses based on prospective cohort studies or trials. 48,[52][53][54][55][56][57] One study took a third party funder perspective, 52 ; no other study described the perspective. [46][47][48][49][50][51][53][54][55][56][57] Time horizons were short-term, with all studies examining an endpoint of initial discharge from hospital. Methodological quality was generally low (10 studies) with two studies of moderate quality − most provided no perspective or decision model, and few reported assumptions or performed uncertainty analyses.
Of the five studies examining tocolysis for recurrent preterm labour, subcutaneous terbutaline was found to be the dominant intervention in significantly increasing gestational age at birth, decreasing neonatal morbidity and decreasing overall costs when compared to oral tocolytics, 46,47 oral nifedipine, 49,50 or no outpatient therapy following stabilisation (Table 5). 48 Ambrose et al (2004) found that outpatient subcutaneous terbutaline was dominant compared to inpatient administration, with later gestation ages at birth, lower preterm birth rates, and lower overall costs. 51 Vald es et al (2012) found that while nifedipine and fenoterol achieved similar tocolytic effects, nifedipine was more likely to fail as a first-line agent, though fenoterol had more adverse reactions; costs were equivalent for both drugs. 53 Jakovljevic et al (2008) found that when comparing acute and maintenance regimens using ritodrine and fenoterol (both betamimetics), the difference in tocolysis time and costs were not different (generating similar incremental cost-effectiveness ratios), although they suggested these findings might be specific to the Serbian healthcare context. 52 Tomczyk et al (2015) found no significant differences in costs or effects between continuous fenoterol and fenoterol for 48-72 hours only. 54 Morales et al (1989) found that indomethacin and ritodrine were equivalent in efficacy, but ritodrine was significantly more expensive than indomethacin ($33 per patient vs $560 per patient in drug and monitoring costs alone). 55 Of the two studies comparing tocolysis with no tocolysis, Korenbrot et al (1984) found that acute and maintenance betamimetic tocolysis was dominant between 26-33 weeks compared to no tocolysis, with better outcomes and lower costs; 56 Weiner et al (1988) did not find any significant difference in costs or outcomes between aggressive tocolysis (ritodrine, terbutaline, or magnesium sulphate) and oral maintenance therapy compared to bed rest. 57

Cost-effectiveness studies of ACS and tocolytics in combination
Four studies were identified which compared different test-treatment combination strategies for preterm labour; data were extracted and compared for strategies that combined ACS and tocolytics without testing ("treat all"), and no treatment or testing ("treat none"); 58-61 one study also compared these options to ACS only. 60 Two studies performed decision modelling and cost-effectiveness analysis based on the APOSTEL-I and APOS-TEL-II trials which compared nifedipine to placebo. One study specified use of effectiveness data for betamimetics, and one study based their analysis on a systematic review of multiple tocolytics. No study specified which type of ACS was used. All four studies were conducted in high-income countries (Netherlands, 58,59 United States, 61 Canada 60 ) and constructed decision models from published data. All studies used short time       horizons, such as hospitalisation until discharge [58][59][60] or up to 7 days. 61 Analytical perspectives were third-party payer, 60 provider, 61 health sector, 58 and societal. 59 Methodological quality was high for all four studies. Mozurkewich et al (2000) found that "treat none" was both more expensive and had higher rates of morbidity and mortality compared to "treat all" (ACS and tocolytics) or universal administration of ACS without tocolysis. Universal ACS only was the least expensive option, but resulted in more deaths and cases of RDS than universal ACS with tocolysis. 60 Myers et al (1997) also found that "treat all" was dominant compared to "treat none" at probabilities of RDS > 2%, with lower costs and better outcomes. 61 Van Baaren et al (2013 and 2018) found that "treat all" had increased costs but fewer deaths and adverse outcomes compared to "treat none" in two studies using different cost perspectives. 58,59 Table 6 shows cost per patient treated, perinatal mortalities and adverse outcomes reported separately for each intervention in three studies, [58][59][60] and cost-effectiveness ratios in one study. 61

Discussion
This is the first systematic review examining the costeffectiveness of ACS and tocolytics in the context of preterm birth management, either alone or in combination. We identified 35 studies, mostly conducted in high-income countries. Studies were of varying methodological quality, and used diverse study designs and methodological approaches. Those pertaining to tocolytics considered a variety of agents, some of which are not in widespread use in contemporary obstetric practice. Studies generally used short-term time horizons, and thus may not accurately reflect longer term health effects or consider all aspects of cost-effectiveness.
Available evidence suggests that ACS is probably cost-saving or cost-effective when administered to women at imminent risk of preterm birth prior to 34 weeks' gestation, though the magnitude of its economic effects probably varies between settings. The 2015 WHO recommends ACS (dexamethasone or betamethasone) for women at risk of imminent preterm birth between 24 to 34 weeks' gestation, provided that certain treatment criteria are met. 5 The current review corroborates this recommendation, as the intervention is likely to be cost-effective in this gestational age range. While Simpson and Lynch initially hypothesised that ACS may increase hospitalisation costs by increasing newborn survival, their own study refuted this. 28 Conversely, WHO does not recommend ACS for late preterm birth as there is still uncertainties about the balance between risks and benefits, 5 though some highresource countries have moved in favour of its use on the basis of the 2016 ALPS trial. [63][64][65] We found conflicting evidence from the USA as to whether this practice is likely to be cost-effective. Conclusions varied from ACS being dominant, cost-effective or dominated compared to no ACS, depending whether a full course was administered, and which newborn health outcomes were evaluated. 32,34,66 The conflicting results reported by two studies using the same trial data illustrates the impact of study design and scope on cost-effectiveness outcomes. 32,34 Given the methodological diversity of cost-effectiveness studies involving tocolytics, it was not possible to identify the best option(s) from an economic perspective. There was no clear consensus as to which tocolytic is economically superior when used to delay birth by at least 48 hours to facilitate ACS administration. Notably, older studies considered tocolytic options such as injectable terbutaline and magnesium sulfate; terbutaline has since been given a black box warning by the Food and Drug Administration, 67 and a 2014 Cochrane review suggests magnesium sulfate is not an effective tocolytic agent. 15 Studies in the current review suggest that when subcutaneous terbutaline is used for maintenance tocolysis, it not only prolongs pregnancy but decreases neonatal morbidity and costs when compared to oral tocolytics or placebo; however, these studies were of low methodological quality, several used the same data source, and maternal side effects were not considered. [46][47][48][49][50] In addition, the efficacy of maintenance tocolysis in terms of health benefits to the neonate is itself uncertain. 5,68 ACS and tocolytics are often used in combination in clinical care, and several studies considered the costeffectiveness of this combination. While available studies indicated that women treated with both interventions generally had better health outcomes than no treatment, studies disagreed as to whether the combination of the two treatments saved or added costs; ACS and tocolytics in combination may nevertheless be costeffective depending on decision-makers' willingness-topay.
Strengths of this systematic review include the use of a broad search strategy across multiple databases, augmented by additional reference checks. We adhered to PRISMA guidance in terms of duplicate screening, data extraction and quality assessment − the latter conducted using the CHEERS checklist recommended by Cochrane. 23 A limitation of this review is the inherent difficulty of comparing cost-effectiveness studies which differ greatly in terms of model composition, data sources, time horizons, outcomes examined, currency, and year of costs, as well as reflecting a diversity of health systems and payment arrangements. 69 Notably, studies used different definitions of preterm labour and newborn health outcomes, limiting the opportunity to synthesise findings. We could not calculate a statistical measure of this heterogeneity as we did not produce pooled estimates, however we assume that heterogeneity is high given the differences between included studies in participants, interventions, outcomes and study design. Dominant if probability of RDS is >2% "Treat all" was cost saving and more effective compared with no treatment at probabilities of RDS above 2%. It may be cost-effective to use no treatment at probabilities of RDS less than 2%. Sensitivity analysis indicated "Treat all" was more cost effective as the costs of RDS and preterm birth increased.
van Baaren 2013 58 Tocolysis and steroids with tertiary centre transfer ("treat all" reference strategy) More effective and more costly than comparator "Treat all" (strategy 1) is more effective and more costly than no treatment (strategy 7). Confidence intervals are not reported for the comparison between these two studies, so statistical significance cannot be determined. A number of included studies were quite old (9 studies were published prior to 2000), hence caution should be taken in generalizing these findings to contemporary health services, considering that treatment options, clinical decision-making, costs and payer arrangements can change over time. However, it was notable that studies that assessed ACS prior to 34 weeks' gestation both before and after 2000 concluded that it was dominant. For tocolytics, we identified no studies of nifedipine or atosiban prior to 2000. While studies may conclude an intervention is cost-effective or cost-saving, this may not generalise to other settings (especially limited-resource settings) with different payer arrangements, higher costs of labour, hospital admission, supplies or equipment, or settings with more contemporary healthcare services. Some ACS and tocolytic options − such as betamethasone and atosiban − are not routinely available or used in many countries.
Further, robust cost-effectiveness studies are needed for these critical interventions in the context of preterm birth management. This review indicates ACS prior to 34 weeks' gestation appears to be cost-effective, which can inform the decision-making of policymakers and maternal health program administrators on resource allocation, particularly in high income countries. Additional confirmatory evidence − particularly for limitedresource settings, where the burden of preterm-associated newborn mortality is often greater − would be useful to support ACS implementation and scale-up activities. Regarding ACS use between 34 and <37 weeks' gestation, the conflicting economic evidence reflects the underlying uncertainty regarding health benefit (reduced respiratory morbidity) and harm (neonatal hypoglycaemia) trade-offs. The ALPS trial was conducted in tertiary care hospitals in the USA and it is not yet clear if the findings are applicable to lower-resource settings. 70 If the health benefit-harm profile is more clearly established through additional trials, future costeffectiveness analyses will be better positioned to fully evaluate the economic implications. In addition, observational studies have recently reported longer-term harms associated with ACS use, particularly when ACSexposed babies are born at term or near-term, 71,72 highlighting the importance of considering longer-term outcomes in future cost-benefit analyses. Such analyses would ideally explore how ACS cost-effectiveness might vary for different weeks of gestation.
The 2015 WHO guidelines indicate that if tocolytics are used, oral nifedipine is the preferred first-line option; 5 however, on the basis of available evidence we were not able to determine if nifedipine was more costeffective than other tocolytics. Future economic evaluations should consider the cost-effectiveness of tocolytics that have been shown to have superior clinical effects (such as nifedipine or atosiban). Such analyses could also consider the cost-effectiveness of these specific tocolytics and ACS alone or in combination. This systematic review was conducted in the context of updating WHO's 2015 recommendations on ACS and tocolytics for preterm birth, 73 and will thus support WHO guideline developers and panels to make evidence-informed judgements on resource use and costeffectiveness.
Available cost-effectiveness studies suggest ACS prior to 34 weeks' gestation in women at risk of imminent preterm birth are probably cost-effective, while findings on the cost-effectiveness of ACS at 34 to <37 weeks' gestation are contradictory depending on which newborn health outcomes are considered. While there are diverse cost-effectiveness studies for different types and indications for tocolysis, the available evidence is insufficient to conclude which tocolytic is superior in terms of cost-effectiveness. Further studies are needed, particularly for tocolytics alone and ACS and tocolytics in combination.

Data sharing statement
All data extracted from studies identified in this review are available in the Supplementary Appendix.

Supplementary materials
Supplementary material associated with this article can be found in the online version at doi:10.1016/j. eclinm.2022.101496.